The present invention is directed to compounds for treating inflammatory bowel disease. More specifically, the present invention is directed to 1H-indole-3-glyoxylamide compounds as sPLA2 inhibitors for treating inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a term that classifies a group of chronic inflammatory disorders involving the gastrointestinal tract. While the exact cause of these diseases are unknown, they exhibit features that permit diagnosis in most cases. Inflammatory bowel disease is inclusive of two main disease states: ulcerative colitis(UC) and Crohn""s disease(DC). The possible treatment effects of sPLA2 inhibitor compounds on ulcerative colitis and Crohn""s disease states have been variously enumerated(see, Peterson, et al., Gut, 39(5): 698-704 (1996), Murthy, et al., Inflammation 16(3): 259-71 (1992), Hastings, et al., Am. Famil. Physician 47(3): 598-608 (1993)).
Claims to the use of sPLA2 inhibitors can be found in the following patent documents: WO 98/18464; WO 96/20959; WO 95/02588A; WO 93/24492A; WO 92/21644A; European Patent Apln. Publ. no. 0675110.
Possible causes that have been advanced for IBD include genetic, infectious, immunologic and psychological. While the exact etiology of the disease is unknown, it is believed that the manifestation of this disease state is a result of immune response within the epithelial and/or the endothelial cells in the colon to external stimuli.
Ulcerative colitis involves an inflammatory reaction affecting the colon. The colon appears ulcerated and hemorrhaged. The inflammation is generally uniform and continuous and often involves the rectum. The major symptoms of ulcerative colitis include bloody diarrhea or constipation, abdominal pain, signs of dehydration, anemia, fever and weight loss. Extracolonic manifestations may include athritis, evidence of liver disease, skin disease and lung disease.
Crohn""s disease is characterized by inflammation extending through all layers of the intestinal wall and often including the mesenteric lymph nodes. The inflammations may penetrate the mucosa and coalesce to form channels called fistulas and fissures. In Crohn""s disease inflammations of the bowel are often discontinues and often granulomatous (see Harrison""s Principles of Internal Medicine, thirteenth ed., 1994, by McGraw-Hill, Inc., ISBN 0-07-032370-4, pg., 1403-1416).
Treatment options include surgical removal of affected tissue often with attendant reconstructive procedures to enable waste removal. Surgical procedures are expensive, inconvenient and often not curative as relapses and new infected sites may be manifested. Medical treatments include but are not limited to administration of corticosteroids, sulfasalazine, 5-amino salicylic acids (5-ASA,), azathioprene, 6-mercaptopurine (6-MP). These treatments are focused on the amelioration of the inflammatory response.
There is a great need for specific and effective treatment of IBD (Sutherland CMAJ 137; 799-802, 1987).
It is an object of the present invention to provide a new methodology for effective treatment of inflammatory bowel disease.
This invention is for the treatment of inflammatory bowel disease in a mammal, including a human, by administering a therapeutically effective amount of 1H-indole-3-glyoxylamide sPLA2 inhibitors.
This invention is also a method for preventing inflammatory bowel disease in a mammal, including a human, by administering a therapeutically effective amount of an 1H-indole-3-glyoxylamide sPLA2 inhibitor.
This invention is also the use of 1H-indole-3-glyoxylamide sPLA2 inhibitors to reduce the complications of acute or chronic infections of the intestine in a human afflicted with gastric and duodenal ulcers adjunctive to inflammatory bowel disease.
This invention is also a method for the treatment of a mammal, including humans, afflicted with inflammatory bowel disease by the use of 1H-indole-3-glyoxylamide sPLA2 inhibitors in combination with other IBD treatment compounds.
This invention is also the use of 1H-indole-3-glyoxylamide sPLA2 inhibitor compounds for the manufacture of medicaments for the treatment of inflammatory bowel disease.
This invention is also a formulation for treatment of IBD comprising (i) an 1H-indole-3-glyoxylamide sPLA2 inhibitor; and (ii) one or more other IBD treatment compounds; and (iii) a carrier or diluent